Thousands of people every year experience long-term or lifelong disabilities in motor, sensory, and cognitive function as result of central nervous system (CNS) injuries. There has been little hope for recovery from these dysfunctions because axons from injured neurons in the brain and spinal cord do not regenerate. A major impediment to regeneration is the formation of a glial scar that expresses axon growth inhibiting molecules like chondroitin sulfate proteoglycans (CSPGs). Novel technologies that can overcome the inhibitory effects of CSPGs could lead to major advancements in therapies that promote functional recovery after CNS injury. In this SBIR project, an innovative panel of cell permeant peptidomimetics will be developed that manipulate the activity of cytoskeletal proteins implicated in the axon growth cone responses to CSPGs. In Phase I, the efficacy of this approach will be tested by developing technologies that manipulate the activity of cofilin, an important cytoskeletal protein in CSPG-activated signaling pathways. Fluorescence microscopy assays will be used to select an optimal peptide transport system for neurons. In vitro biochemical assays will be used to screen cofilin-related peptides (CRPs) designed to manipulate cofilin protein activities. Growth cone motility assays will be used to assess the efficacy of the selected peptide transport system and CRP peptides for altering cofilin activity in a manner that promotes axon growth across CSPG containing borders. In Phase II, the methods and technologies developed in Phase I will be used to create a panel of cell-permeant peptidomimetics that can regulate the activity of a variety of cytoskeletal proteins implicated in the growth cone responses to CSPGs. These peptidomimetics will be commercialized by ECM Biosciences in two ways, as novel protein-manipulating research tools and as new therapeutic strategies for promoting functional recovery from CNS injuries. Project Relevance Currently, there are limited therapeutic strategies for promoting recovery from central nervous system (CNS) injuries. A major factor limiting the development of therapies that promote recovery from CNS injuries is the difficulty promoting axon regeneration in the injured region. Advancements in the molecular tools used to study axon growth and regeneration is critical for new discoveries of the mechanisms involved with repair of the injured CNS. This SBIR proposal will facilitate the development of novel peptidomimetic technologies that can be used to manipulate protein function in neurons in vivo. These technologies will target proteins critical for axon outgrowth in an attempt to produce unique tools for studying axon regeneration. More importantly these research tools may lead to the development of agents that can promote axon regeneration in the injured CNS. Thus, successful development of peptidomimetic technologies in this SBIR proposal will significantly advance axon regeneration research and could lead to the discovery of novel therapeutic strategies for promoting recovery from CNS injuries. [unreadable] [unreadable] [unreadable]